Increasing procaspase 8 expression using repurposed drugs to induce HIV infected cell death in ex vivo patient cells

PloS One
Rahul SampathAndrew D Badley

Abstract

HIV persists because a reservoir of latently infected CD4 T cells do not express viral proteins and are indistinguishable from uninfected cells. One approach to HIV cure suggests that reactivating HIV will activate cytotoxic pathways; yet when tested in vivo, reactivating cells do not die sufficiently to reduce cell-associated HIV DNA levels. We recently showed that following reactivation from latency, HIV infected cells generate the HIV specific cytotoxic protein Casp8p41 which is produced by HIV protease cleaving procaspase 8. However, cell death is prevented, possibly due to low procaspase 8 expression. Here, we tested whether increasing procaspase 8 levels in CD4 T cells will produce more Casp8p41 following HIV reactivation, causing more reactivated cells to die. Screening 1277 FDA approved drugs identified 168 that increased procaspase 8 expression by at least 1.7-fold. Of these 30 were tested for anti-HIV effects in an acute HIVIIIb infection model, and 9 drugs at physiologic relevant levels significantly reduced cell-associated HIV DNA. Primary CD4 T cells from ART suppressed HIV patients were treated with one of these 9 drugs and reactivated with αCD3/αCD28. Four drugs significantly increased Casp8p41 levels following H...Continue Reading

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Citations

Oct 30, 2019·AIDS Research and Human Retroviruses·Ana C PaimNathan W Cummins
Dec 19, 2019·Pharmaceutics·Andrés GonzálezÁngel Lanas

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Methods Mentioned

BETA
leukapheresis
ELISA
PCR
transfections
PMA
FACS

Software Mentioned

GraphPad Prism
FlowJo

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